Ligand-accelerated non-directed C-H functionalization of arenes.

The directed activation of carbon-hydrogen bonds (C-H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups. Palladium-catalysed non-directed C-H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges associated with the lack of sufficiently active palladium catalysts. Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used, which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C-H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of aromatic substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug molecules and natural products that cannot be used in excessive quantities. We also developed C-H olefination and carboxylation protocols, demonstrating the applicability of our methodology to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C-H functionalization.

Ligand-Enabled meta-Selective C-H Arylation of Nosyl-Protected Phenethylamines, Benzylamines, and 2-Aryl Anilines.

A Pd-catalyzed, meta-selective C-H arylation of nosyl-protected phenethylamines and benzylamines is disclosed using a combination of norbornene and pyridine-based ligands. Subjecting nosyl protected 2-aryl anilines to this protocol led to meta-C-H arylation at the remote aryl ring. A diverse range of aryl iodides are tolerated in this reaction, along with select heteroaryl iodides. Select aryl bromides bearing ortho-coordinating groups can also be utilized as effective coupling partners in this reaction. The use of pyridine ligands has allowed the palladium loading to be reduced to 2.5 mol %. Furthermore, a catalytic amount of 2-norbornene (20 mol %) to mediate this meta-C-H activation process is demonstrated for the first time. Utilization of a common protecting group as the directing group for meta-C-H activation of amines is an important feature of this reaction in terms of practical applications.

Rh(III)-Catalyzed meta-C-H Olefination Directed by a Nitrile Template.

A range of Rh(III)-catalyzed ortho-C-H functionalizations have been developed; however, extension of this reactivity to remote C-H functionalizations through large-ring rhodacyclic intermediates has yet to be demonstrated. Herein we report the first example of the use of a U-shaped nitrile template to direct Rh(III)-catalyzed remote meta-C-H activation via a postulated 12-membered macrocyclic intermediate. Because the ligands used for Rh(III) catalysts are significantly different from those of Pd(II) catalysts, this offers new opportunities for future development of ligand-promoted meta-C-H activation reactions.

Ligand-Promoted meta-C-H Functionalization of Benzylamines.

Meta-C-H functionalization of benzylamines has been developed using a PdII /transient mediator strategy. Using 2-pyridone ligands and 2-carbomethoxynorbornene (NBE-CO2 Me) as the mediator, arylation, amination, and chlorination of benzylamines are realized. This protocol features a broad substrate scope and is compatible with heterocylic coupling partners. Moreover, the loading of the Pd can be lowered to 2.5 mol % by using the optimal ligand.

Ligand-Enabled Auxiliary-Free meta-C-H Arylation of Phenylacetic Acids.

The meta-C-H arylation of free phenylacetic acid was realized using 2-carbomethoxynorbornene (NBE-CO2 Me) as a transient mediator. Both the modified norbornene and the mono-protected 3-amino-2-hydroxypyridine type ligand are crucial for this auxiliary-free meta-C-H arylation reaction. A series of phenylacetic acids, including mandelic acid and phenylglycine, react smoothly with various aryl iodides to provide the meta-arylated products in high yields.

Ligand Promoted meta-C-H Chlorination of Anilines and Phenols.

Pd-catalyzed meta-C-H chlorination of anilines and phenols is developed using norbornene as the mediator. Heterocycles, including indole, thiophene, and indazole, are tolerated. The identification of a new pyridone-based ligand is crucial for the success of this meta-C-H chlorination reaction. Subsequent diverse transformations of the chlorinated products demonstrate the versatility of meta-C-H chlorination.

Ligand-Promoted meta-C-H Amination and Alkynylation.

Using a modified norbornene (methyl bicyclo[2.2.1]hept-2-ene-2-carboxylate) as a transient mediator, meta-C-H amination and meta-C-H alkynylation of aniline and phenol substrates have been developed for the first time. Both the identification of a monoprotected 3-amino-2-hydroxypyridine/pyridone-type ligand and the use of a modified norbornene as a mediator are crucial for the realization of these two unprecedented meta-C-H transformations. A variety of substrates are compatible with both meta-C-H amination and meta-C-H alkynylation. Amination and alkynylation of heterocyclic substrates including indole, indoline, and indazole afford the desired products in moderate to high yields.

Ligand-Promoted Meta-C-H Arylation of Anilines, Phenols, and Heterocycles.

Here we report the development of a versatile 3-acetylamino-2-hydroxypyridine class of ligands that promote meta-C-H arylation of anilines, heterocyclic aromatic amines, phenols, and 2-benzyl heterocycles using norbornene as a transient mediator. More than 120 examples are presented, demonstrating this ligand scaffold enables a wide substrate and coupling partner scope. Meta-C-H arylation with heterocyclic aryl iodides as coupling partners is also realized for the first time using this ligand. The utility for this transformation for drug discovery is showcased by allowing the meta-C-H arylation of a lenalidomide derivative. The first steps toward a silver-free protocol for this reaction are also demonstrated.

A Simple and Versatile Amide Directing Group for C-H Functionalizations.

Achieving selective C-H activation at a single and strategic site in the presence of multiple C-H bonds can provide a powerful and generally useful retrosynthetic disconnection. In this context, a directing group serves as a compass to guide the transition metal to C-H bonds by using distance and geometry as powerful recognition parameters to distinguish between proximal and distal C-H bonds. However, the installation and removal of directing groups is a practical drawback. To improve the utility of this approach, one can seek solutions in three directions: 1) Simplifying the directing group, 2) using common functional groups or protecting groups as directing groups, and 3) attaching the directing group to substrates via a transient covalent bond to render the directing group catalytic. This Review describes the rational development of an extremely simple and yet broadly applicable directing group for Pd(II) , Rh(III) , and Ru(II) catalysts, namely the N-methoxy amide (CONHOMe) moiety. Through collective efforts in the community, a wide range of C-H activation transformations using this type of simple directing group have been developed.

Monoselective o-C-H Functionalizations of Mandelic Acid and α-Phenylglycine.

Pd-catalyzed C-H functionalization of mandelic acid and α-phenylglycine is reported. We have developed different protocols for the arylation, iodination, acetoxylation, and olefination of these substrates based on two different (Pd(II)/Pd(IV) and Pd(II)/Pd(0)) catalytic cycles. Four crucial features of these protocols are advantageous for practical applications. First, the α-hydroxyl and amino groups are protected with simple protecting groups such as acetates (Ac, Piv) and carbamates (Boc, Fmoc), respectively. Second, these protocols do not involve installation and removal of a directing group. Third, monoselectivity is accomplished. Fourth, no epimerization occurs at the vulnerable α-chiral centers.

Unlocking nature's C-H bonds.

In an idealistic setting, it can be imagined that if every CH bond on an organic molecule could be selectively functionalized, the fields of chemical synthesis and drug discovery would be forever revolutionized. With the purpose of investigating the practicality of this idealistic scenario, our group has endeavored to unlock the potential of nature's CH bonds by developing palladium-catalyzed, site selective CH insertions that can be incorporated into both known and new catalytic cycles. To this end, we have developed a number of catalytic transformations that not only provide rapid diversification of simple starting materials and natural products through CH functionalization, but streamline the synthesis of a variety of natural products with biological activity and expand upon methods to access highly valuable enantiopure materials.

Palladium Catalyzed meta-C-H Functionalization of Masked Aromatic Aldehydes.

Palladium catalyzed meta-C-H functionalization enabled by transient mediators has the potential to extend the utility of directed ortho-C-H functionalization to remote positions. However, there have been no reports of palladium catalyzed meta-C-H functionalization of aromatic aldehyde derivatives, which are highly versatile intermediates in organic synthesis. Herein we report the development of a directing group that, in the presence of a norbornene derived mediator and an appropriate pyridone ligand, allows palladium catalyzed meta-C-H functionalization of masked aromatic aldehydes. Mechanistic insight regarding the impact of the directing group length on this catalysis is also discussed.